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e278S

CHEST Supplement

Prevention of VTE in Orthopedic Surgery Patients

ANTITHROMBOTIC THERAPY AND PREVENTION OF THROMBOSIS, 9TH ED: ACCP GUIDELINES

Background: VTE is a serious, but decreasing complication following major orthopedic surgery.This guideline focuses on optimal prophylaxis to reduce postoperative pulmonary embolism andDVT.

Methods: The methods of this guideline follow those described in Methodology for the Develop-ment of Antithrombotic Therapy and Prevention of Thrombosis Guidelines: Antithrombotic Therapyand Prevention of Thrombosis, 9th ed: American College of Chest Physicians Evidence-BasedClinical Practice Guidelines in this supplement.

Results: In patients undergoing major orthopedic surgery, we recommend the use of one of thefollowing rather than no antithrombotic prophylaxis: low-molecular-weight heparin; fondaparinux;dabigatran, apixaban, rivaroxaban (total hip arthroplasty or total knee arthroplasty but not hipfracture surgery); low-dose unfractionated heparin; adjusted-dose vitamin K antagonist; aspirin(all Grade 1B); or an intermittent pneumatic compression device (IPCD) (Grade 1C) for a min-imum of 10 to 14 days. We suggest the use of low-molecular-weight heparin in preference to the other

agents we have recommended as alternatives (Grade 2C/2B), and in patients receiving pharma-cologic prophylaxis, we suggest adding an IPCD during the hospital stay (Grade 2C). We suggestextending thromboprophylaxis for up to 35 days (Grade 2B). In patients at increased bleeding risk, wesuggest an IPCD or no prophylaxis (Grade 2C). In patients who decline injections, we recom-mend using apixaban or dabigatran (all Grade 1B). We suggest against using inferior vena cavafilter placement for primary prevention in patients with contraindications to both pharmacologicand mechanical thromboprophylaxis (Grade 2C). We recommend against Doppler (or duplex)ultrasonography screening before hospital discharge (Grade 1B). For patients with isolated lower-extremity injuries requiring leg immobilization, we suggest no thromboprophylaxis (Grade 2B).For patients undergoing knee arthroscopy without a history of VTE, we suggest no thromboprophy-laxis (Grade 2B).Conclusions: Optimal strategies for thromboprophylaxis after major orthopedic surgery includepharmacologic and mechanical approaches. CHEST 2012; 141(2)(Suppl):e278S–e325S

Abbreviations: DUS5Doppler (or duplex) ultrasonography; GCS5graduated compression stockings; HFS5hipfracture surgery; INR5 international normalized ratio; IPCD5 intermittent pneumatic compression device; IVC5 infe-rior vena cava; LDUH5 low-dose unfractionated heparin; LMWH5 low-molecular-weight heparin; PE5pulmonaryembolism; PEP5Pulmonary Embolism Prevention trial; RCT5randomized controlled trial; RR5risk ratio; THA5total hiparthroplasty; TKA5 total knee arthroplasty; UFH5unfractionated heparin; VFP5 venous foot pump; VKA5 vitaminK antagonist

Prevention of VTE in OrthopedicSurgery Patients

Antithrombotic Therapy and Prevention of Thrombosis,

9th ed: American College of Chest Physicians

Evidence-Based Clinical Practice Guidelines

Yngve Falck-Ytter , MD ; Charles W. Francis , MD ; Norman A. Johanson , MD ;Catherine Curley , MD ; Ola E. Dahl , MD ; Sam Schulman , MD, PhD ;Thomas L. Ortel , MD, PhD ; Stephen G. Pauker , MD ; and Clifford W. Colwell Jr , MD

wnloaded From: http://journal.publications.chestnet.org/ on 04/17/2016

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www.chestpubs.org CHEST / 141 / 2 / FEBRUARY, 2012 SUPPLEMENT e279S

reporting proper wear time on a daily basis for inpa-tients and outpatients. Efforts should be made toachieve 18 h of daily compliance. One panel memberbelieved strongly that aspirin alone should not beincluded as an option.

2.1.2. In patients undergoing hip fracture sur-gery (HFS), we recommend use of one of the

following rather than no antithrombotic prophy-laxis for a minimum of 10 to 14 days: LMWH,fondaparinux, LDUH, adjusted-dose VKA, aspi-rin (all Grade 1B), or an IPCD (Grade 1C).

Remarks: We recommend the use of only portable,battery-powered IPCDs capable of recording andreporting proper wear time on a daily basis for inpa-tients and outpatients. Efforts should be made toachieve 18 h of daily compliance. One panel memberbelieved strongly that aspirin alone should not beincluded as an option.

2.2. For patients undergoing major orthopedicsurgery (THA, TKA, HFS) and receiving LMWHas thromboprophylaxis, we recommend startingeither 12 h or more preoperatively or 12 h ormore postoperatively rather than within 4 h orless preoperatively or 4 h or less postoperatively (Grade 1B).

2.3.1. In patients undergoing THA or TKA, irre-spective of the concomitant use of an IPCDor length of treatment, we suggest the use ofLMWH in preference to the other agents we haverecommended as alternatives: fondaparinux,apixaban, dabigatran, rivaroxaban, LDUH (allGrade 2B), adjusted-dose VKA, or aspirin (allGrade 2C).

Remarks: If started preoperatively, we suggest adminis-tering LMWH 12 h before surgery. Patients whoplace a high value on avoiding the inconvenience ofdaily injections with LMWH and a low value on thelimitations of alternative agents are likely to choosean alternative agent. Limitations of alternative agentsinclude the possibility of increased bleeding (whichmay occur with fondaparinux, rivaroxaban, and VKA),

possible decreased efficacy (LDUH, VKA, aspirin, andIPCD alone), and lack of long-term safety data (apixa-ban, dabigatran, and rivaroxaban). Furthermore, patients who place a high value on avoiding bleeding compli-cations and a low value on its inconvenience are likelyto choose an IPCD over the drug options.

2.3.2. In patients undergoing HFS, irrespectiveof the concomitant use of an IPCD or lengthof treatment, we suggest the use of LMWH inpreference to the other agents we have recom-mended as alternatives: fondaparinux, LDUH

Revision accepted August 31, 2011. Affiliations: From the Department of Medicine (Dr Falck-Ytter),School of Medicine, Case Western Reserve University, Cleveland,OH; Hematology/Oncology Unit (Dr Francis), University of Roches-ter Medical Center, Rochester, NY; Department of OrthopaedicSurgery (Dr Johanson), Drexel University College of Medicine,Philadelphia, PA; Division of Hospital Medicine (Dr Curley),

MetroHealth Medical Center, Case Western Reserve University,Cleveland, OH; Innlandet Hospitals (Dr Dahl), Brumunddal,Norway; Thrombosis Research Institute (Dr Dahl), Chelsea,London, England; Department of Medicine (Dr Schulman), Divi-sion of Hematology and Thromboembolism, McMaster University,Hamilton, ON, Canada; Hemostasis and Thrombosis Center(Dr Ortel), Duke University Health System, Durham, NC; TuftsMedical Center (Dr Pauker), Boston, MA; and Shiley Center forOrthopaedic Research and Education at Scripps Clinic (Dr Colwell),La Jolla, CA.Funding/Support : The Antithrombotic Therapy and Preventionof Thrombosis, 9th ed: American College of Chest PhysiciansEvidence-Based Clinical Practice Guidelines received support fromthe National Heart, Lung, and Blood Institute [R13 HL104758]and Bayer Schering Pharma AG. Support in the form of educa-tional grants was also provided by Bristol-Myers Squibb; Pfizer,

Inc; Canyon Pharmaceuticals; and sanofi-aventis US.Disclaimer: American College of Chest Physician guidelinesare intended for general information only, are not medical advice,and do not replace professional medical care and physician advice,

which always should be sought for any medical condition. Thecomplete disclaimer for this guideline can be accessed at http:// chestjournal.chestpubs.org/content/141/2_suppl/1S. Correspondence to: Yngve Falck-Ytter, MD, Department ofMedicine, School of Medicine, Case Western Reserve University,Case and VA Medical Center, 10701 East Blvd, Cleveland, OH44106; e-mail: [email protected]© 2012 American College of Chest Physicians. Reproductionof this article is prohibited without written permission from theAmerican College of Chest Physicians ( http://www.chestpubs.org/ site/misc/reprints.xhtml).DOI: 10.1378/chest.11-2404

Summary of Recommendations

Note on Shaded Text: Throughout this guideline,shading is used within the summary of recommenda-tions sections to indicate recommendations that arenewly added or have been changed since the pub-lication of Antithrombotic and Thrombolytic Therapy:American College of Chest Physicians Evidence-Based Clinical Practice Guidelines (8th Edition). Rec-ommendations that remain unchanged are not shaded.

2.1.1. In patients undergoing total hip arthro-plasty (THA) or total knee arthroplasty (TKA),

we recommend use of one of the following for aminimum of 10 to 14 days rather than no anti-thrombotic prophylaxis: low-molecular-weightheparin (LMWH), fondaparinux, apixaban, dab-igatran, rivaroxaban, low-dose unfractionatedheparin (LDUH), adjusted-dose vitamin K antag-onist (VKA), aspirin (all Grade 1B), or an inter-

mittent pneumatic compression device (IPCD) (Grade 1C).

Remarks: We recommend the use of only portable,battery-powered IPCDs capable of recording and


http://www.chestpubs.org/http://chestjournal.chestpubs.org/content/141/2_suppl/1Shttp://chestjournal.chestpubs.org/content/141/2_suppl/1Smailto:[email protected]://www.chestpubs.org/site/misc/reprints.xhtmlhttp://www.chestpubs.org/site/misc/reprints.xhtmlhttp://www.chestpubs.org/site/misc/reprints.xhtmlhttp://www.chestpubs.org/site/misc/reprints.xhtmlhttp://www.chestpubs.org/http://www.chestpubs.org/site/misc/reprints.xhtmlhttp://www.chestpubs.org/site/misc/reprints.xhtmlmailto:[email protected]://chestjournal.chestpubs.org/content/141/2_suppl/1Shttp://chestjournal.chestpubs.org/content/141/2_suppl/1S

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e280S Prevention of VTE in Orthopedic Surgery Patients

2.7. In patients undergoing major orthopedicsurgery and who decline or are uncooperative withinjections or an IPCD, we recommend usingapixaban or dabigatran (alternatively rivaroxa-ban or adjusted-dose VKA if apixaban or dabig-atran are unavailable) rather than alternativeforms of prophylaxis (all Grade 1B).

2.8. In patients undergoing major orthopedicsurgery, we suggest against using inferior venacava (IVC) filter placement for primary pre-vention over no thromboprophylaxis in patients

with an increased bleeding risk or contraindi-cations to both pharmacologic and mechanicalthromboprophylaxis (Grade 2C).

2.9. For asymptomatic patients following majororthopedic surgery, we recommend against Dopp-ler (or duplex) ultrasound (DUS) screening beforehospital discharge (Grade 1B).

3.0. We suggest no prophylaxis rather than phar-macologic thromboprophylaxis in patients withisolated lower-leg injuries requiring leg immo-bilization (Grade 2C).

4.0. For patients undergoing knee arthroscopy without a history of prior VTE, we suggest nothromboprophylaxis rather than prophylaxis (Grade 2B).

Total hip arthroplasty (THA) and total knee arthro-plasty (TKA) are performed with increasing fre-

quency, with close to 200,000 procedures for THAalone in the United States each year.1 The risk for VTE in major orthopedic surgery, in particular THAand hip fracture surgery (HFS), is among the highestfor all surgical specialties, and deaths from VTE stilloccur, albeit very infrequently. This article discussesprophylaxis of VTE in patients undergoing ortho-pedic surgery, including THA, TKA, and HFS; below-knee injuries; and arthroscopic procedures. We haveincluded only the drugs that have been approved byregulatory agencies in more than one country.

1.0 Methods

1.1 Outcomes of Interest

All recommendations are based on the use of prophylaxis toreduce the patient-important outcomes of fatal and symptomaticpulmonary embolism (PE) and symptomatic DVT balanced againstthe hazard of an increase in symptomatic bleeding events. Thedesign and reporting of clinical trials creates challenges in applyingthis approach. Studies have used varying definitions of importantbleeding, and it was sometimes difficult to extract data regardingpatient-important bleeding outcomes (those that led to trans-fusion or an intervention, such as reoperation). Additionally, most

(Grade 2B), adjusted-dose VKA, or aspirin (allGrade 2C).

Remarks: For patients in whom surgery is likely to bedelayed, we suggest that LMWH be initiated duringthe time between hospital admission and surgery butsuggest administering LMWH at least 12 h beforesurgery. Patients who place a high value on avoiding

the inconvenience of daily injections with LMWHand a low value on the limitations of alternative agentsare likely to choose an alternative agent. Limita-tions of alternative agents include the possibility ofincreased bleeding (which may occur with fonda-parinux) or possible decreased efficacy (LDUH, VKA,aspirin, and IPCD alone). Furthermore, patients whoplace a high value on avoiding bleeding complica-tions and a low value on its inconvenience are likelyto choose an IPCD over the drug options.

2.4. For patients undergoing major orthopedic

surgery, we suggest extending thromboprophy-laxis in the outpatient period for up to 35 daysfrom the day of surgery rather than for only10 to 14 days (Grade 2B).

2.5. In patients undergoing major orthopedicsurgery, we suggest using dual prophylaxis withan antithrombotic agent and an IPCD duringthe hospital stay (Grade 2C).

Remarks: We recommend the use of only portable,battery-powered IPCDs capable of recording andreporting proper wear time on a daily basis for inpa-tients and outpatients. Efforts should be made toachieve 18 h of daily compliance. Patients who placea high value on avoiding the undesirable consequencesassociated with prophylaxis with both a pharmaco-logic agent and an IPCD are likely to decline use ofdual prophylaxis.

2.6. In patients undergoing major orthopedicsurgery and increased risk of bleeding, we sug-gest using an IPCD or no prophylaxis ratherthan pharmacologic treatment (Grade 2C).

Remarks: We recommend the use of only portable,battery-powered IPCDs capable of recording andreporting proper wear time on a daily basis for inpa-tients and outpatients. Efforts should be made toachieve 18 h of daily compliance. Patients who placea high value on avoiding the discomfort and inconve-nience of IPCD and a low value on avoiding a smallabsolute increase in bleeding with pharmacologic agents when only one bleeding risk factor is present (in par-ticular the continued use of antiplatelet agents) arelikely to choose pharmacologic thromboprophylaxisover IPCD.


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T a b l e 1 — [ I n t r o d u c t i o n ] S t r u c t u r e d C l i n i c a l Q u e s t i o n s

P I C O Q u e s t i o n

S e c t i o n

I n f o r m a l Q u e s

t i o n

P o p u l a t i o n

I n t e r v e n t i o n s

C o m p a r a t o r

O u t c o m e

M e t h o d o l o g y

M a j o r o r t h o p e d i c

s u r g e r y ( T H A ,

T K A , H F S )

W h e t h e r t o u s e V T E

p r o p h y l a x i s ( d r u g s )

P a t i e n t s u n d e r g o i n g

T H A , T K A , H F S

A

n y d r u g ( L M W H ,

L D U H , f o n d a p a r i n u x ,

V K A , A S A , d a b i g a t r a n ,

r i v a r o x a b a n , a p i x a b a n )

N o a n t i c o a g u l a t i o n

A s y m p t o m a t i c D V T ,

s y m p t o m a t i c D V T , n o n f a t a l P E ,

f a t a l P E , b l e e d i n g , r e o p e

r a t i o n ,

r e a d m i s s i o n , t o t a l m o r t a l i t y

R C T


p r o p h y l a x i s ( m e c h a n i c a l )

S a m e

A

n y m e c h a n i c a l d e v i c e

N o d e v i c e

S a m e

R C T

C h o i c e o f t h r o m b o p r

o p h y l a x i s

d r u g s

S a m e

A

n y d r u g

A n y d r u g

S a m e

R C T

C h o i c e o f m e c h a n i c a l d e v i c e s

v s m e d i c a t i o n s

S a m e

M

e c h a n i c a l d e v i c e s

A n y d r u g

S a m e

R C T

C h o i c e o f c o m b i n i n g

d i f f e r e n t

m e d i c a t i o n o r m e c h a n i c a l

m e t h o d s w i t h d r u g

s

S a m e

C

o m b i n a t i o n o f m u l t i p l e

a g e n t s o r d e v i c e s

S i n g l e i n t e r v e n t i o n o r

c o m b i n a t i o n s

S a m e

R C T

T i m i n g o f s t a r t i n g

t h r o m b o p r o p h y l a x i s

S a m e

1 0 - 1 2 h p r e o p e r a t i v e l y

2 - 4 h p r e o p e r a t i v

e l y ; o r

d i f f e r e n t t i m e p o i n t s

p o s t o p e r a t i v e l y

S a m e

R C T

C h o i c e o f d u r a t i o n

S a m e

3 0 d

7 - 1 4 d

S a m e

R C T

R o l e o f p r e d i s c h a r g e

u l t r a s o u n d D V T s c

r e e n i n g

S a m e

P r e d i s c h a r g e u l t r a s o u n d

D V T s c r e e n i n g ( p l u s

t r e a t m e n t i f p o s i t i v e )

N o s c r e e n i n g

S a m e

R C T

W h e t h e r I V C fi l t e r s h o u l d b e

u s e d i n d e fi n e d p o p u l a t i o n s

S a m e

I V C fi l t e r f o r p r i m a r y

p r e v e n t i o n

N o fi l t e r , a n y o t h e r m e c h a n i c a l

t h r o m b o p r o p h

y l a x i s

S a m e ( p l u s a n y I V C fi l t e r

r e l a t e d e f f e c t s )

R C T , o b s e r v a t i o n a l

s t u d i e s

K n e e a r t h r o s c o p y ,

i s o l a t e d d i s t a l t o

t h e k n e e i n j u r i e s


p r o p h y l a x i s ( d r u g s )

P a t i e n t s u n d e r g o i n g

a r t h r o s c o p i c p r o c e d u r e s ,

p a t i e n t s w i t h i s o l a t e d

d i s t a l - t o - k n e e i n j u r i e s

A

n y d r u g

N o a n t i c o a g u l a t i o n

A s y m p t o m a t i c D V T ,

s y m p t o m a t i c D V T ,

n o n f a t a l P E , f a t a l P E ,

b l e e d i n g , r e o p e r a t i o n ,

r e a d m i s s i o n , t o t a l m o r t a l i t y

R C T


p r o p h y l a x i s ( m e c h a n i c a l )

S a m e

A

n y m e c h a n i c a l d e v i c e

N o d e v i c e

S a m e

R C T

C h o i c e o f t h r o m b o p r

o p h y l a x i s

d r u g s

S a m e

A

n y d r u g

A n y d r u g

S a m e

R C T

C h o i c e o f m e c h a n i c a l

d e v i c e s v s m e d i c a t i o n s

S a m e

M

e c h a n i c a l d e v i c e s

A n y d r u g

S a m e

R C T ?

A S A 5 a s p i r i n ; H F S 5 h

i p f r a c t u r e s u r g e r y ; I V C 5 i n

f e r i o r v e n a c a v a ; L D U H 5 l o w - d o s e u n f r a c t i o n a t e d h e p a r i n ; L M W H 5 l o w - m

o l e c u l a r - w e i g h t h e p a r i n ; P E 5 p u l m o n a r y e

m b o l i s m ; P I C O 5 p o p u l a t i o n ,

i n t e r v e n t i o n , c o m p a r a t o r , o u t c o m e ; R C T 5 r a n d o m i z e d c o n t r o l l e d t r i a l ; T H A 5 t o

t a l h i p a r t h r o p l a s t y ; T K A 5 t o

t a l k n e e a r t h r o p l a s t y ; V K A 5 v

i t a m i n K a n t a g o n i s t .


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bleeding definition of the study but recorded any bleeds requiringreoperation in a separate category to avoid double counting.

Because patients undergoing surgery have some blood lossand surgeons may have a low threshold for transfusing blood whenautologous blood is used (with perioperative transfusion ratesof 40% not being unusual),4 drop in hemoglobin level and trans-fusion requirements are hard to interpret. The effect of suchtransfusion practices on the significance of the outcome of majorbleeding is unknown. However, major bleeding that followed theabove definition appears to have a clinical impact. A regression

analysis of major bleeding events involving . 13,000 patientsenrolled in fondaparinux trials demonstrated a hazard ratio ofdeath of close to 7 (8.6% vs 1.7%), demonstrating a strong rela-tionship between major bleeding and poor outcome irrespectiveof the study drug used.5 Whether this finding can be generalizedto other populations and interventions is unknown.

The major advantage of our outlined approach is that the evi-dence summaries allow for direct trade-off of undesirable events.These trade-offs are fewer symptomatic PE and DVT with throm-boprophylaxis vs increased major bleeding.2

1.3 Deriving Baseline Risks

1.3.1 Baseline Risk for VTE: We made considerable effort to

determine the baseline risk of symptomatic VTE and bleeding inthe absence of prophylaxis. For this purpose, we analyzed all con-trolled trials that had a placebo or no-treatment group extendingback to 1959.6 This has obvious limitations because of importantchanges in surgical care, including changes in operative tech-nique, earlier ambulation, and earlier discharge that have had animpact on rates of thrombosis and bleeding. For instance, althoughthe average length of stay after HFS in the 1960s was 35 days,7 current averages of 3.2 days have been reported in a large cohortafter arthroplasties,8 and early mobilization starts at 2 to 4 h aftersurgery.8 Randomized controlled trial (RCT) data typically showeda symptomatic VTE event rate of 15% to 30% without prophylaxisprior to 1980,6,9-12 and observational data suggest a further dropfrom around 5% to 1% to 2% in the years from 1989 to 2001. 13

In recent years, there have been no large placebo controlledtrials, and we did not identify any large, well-designed cohort stud-ies to provide a baseline risk relevant to current practice. However,there are several large RCTs that have used low-molecular-weightheparin (LMWH), and we have estimated baseline risk by apply-ing the observed risk of symptomatic VTE in patients treated withLMWH and adjusting it by the relative risk reduction in symp-tomatic VTE from prior randomized trials of LMWH compared

with placebo.First, we estimated contemporary average on-prophylaxis

rates with LMWH for symptomatic DVT to be 0.8% and for PEto be 0.35% by averaging the LMWH event rates from trialsenrolling . 16,000 patients since 2003.4,14-26 We selected the year2003 because of a shift in surgical technique since that time tobe less invasive and possibly less thrombogenic. Concerns that

those rates could be too low given the sometimes highly selectednature of clinical trials, we compared this rate with older datafrom a large observational study.27 The investigators identified133 of 19,586 (0.7%) VTE events during the initial hospitalizationfor patients receiving prophylaxis (estimated prophylaxis compli-ance, 88%), suggesting that the symptomatic VTE rate of 1.15%

we used is not too low.Second, if we assume the effect of LMWH is similar in asymp-

tomatic and symptomatic DVT, then the best evidence suggeststhat LWMH reduces the risk for DVT by 50% to 60% and PE byabout two-thirds.3 Using this estimate, the contemporary off-prophylaxis rates are 1.8% for symptomatic DVT and 1% for PEfor the first 7 to 14 days (the initial prophylaxis period most RCTsused and that correspond to the nonextended prophylaxis period).

trials before 2000 used asymptomatic DVT detected by screeningtests as a primary end point. When symptomatic DVTs were notreported, we used the relative risk estimate from asymptomaticDVT. Pulmonary embolisms (PEs) were assumed to be symp-tomatic unless the study described systematic screening for PE. 2 Table 1 summarizes the questions we addressed.

1.2 Evaluating and Summarizing Evidence

If available, we used existing systematic reviews as the basis of

evidence. If existing reviews were unavailable or not up to date orthe outcomes of interest were not reported, we performed addi-tional analyses. For example, we relied on a recent, well-done sys-tematic review3 to inform relative effects of low-dose unfractionatedheparin (LDUH) vs no prophylaxis because studies were per-formed in the 1970s and 1980s and critical appraisal of the searchstrategy made it unlikely that studies would have been missed.However, we performed an update of the same comprehensiveliterature search for all interventions listed in Table 1 to includethe time frame from January 2008 to December 2010. Sourcesincluded Medline, the Cochrane Library (including the Cochranedatabase of controlled trials), meeting abstracts, conferenceproceedings, and reference lists of studies that were manuallyreviewed. No language restriction was applied.

For additional analyses, we pooled the data using a random-effects model for three or more studies (fixed-effects model fortwo studies). When the analysis showed a similar relative effectfor THA, TKA, and HFS, we used this single best relative riskestimate to inform absolute risk differences in VTE reductionand bleeding risk increase. When effects differed, we used effectsspecific to the surgery.

For our own analyses, we excluded studies that failed to con-firm VTE with accurate methods, such as pulmonary angiogram,CT scan, ventilation/perfusion scanning, venography, and com-pression Doppler (or duplex) ultrasonography (DUS), and insteadused clinical signs and symptoms, plethysmography, or fibrinogenuptake as the sole detection method. However, for well-done sys-tematic reviews, we accepted the authors’ choice of study selec-tion, even if a less-reliable detection method was used in some ofthe studies.

Where possible, we removed doubly counted events from theoutcomes presented in the evidence summaries. For instance, if apatient died of a PE, the event would only be counted in mortalityand would not appear again under PE. We report deaths from PEtogether with all other mortal events, but a footnote presents adescription of those events as deaths from VTE, deaths fromunexplained causes (unable to rule out PE), fatal bleeding, anddeath from other causes. Because studies often presented out-comes as composites, the number of events in our analysis mayat times differ from the result highlighted in the publication.

Different categories of bleeding events have very differentimpacts on patients. Trials, therefore, have separated bleedinginto categories, of which traditionally there have been two: major

bleeding and minor bleeding. More recent trials have introducedanother, intermediate category: clinically relevant nonmajor bleed-ing. However, clinically relevant nonmajor bleeding remainshard to define, and we decided not to include this outcome inour evidence summaries, instead exclusively focusing on majorbleeding.

Studies usually defined major bleeding events as any fatal bleed-ing, bleeding into a critical organ (eg, retroperitoneal, intracra-nial, intraocular, or intraspinal), clinically overt (eg, GI) bleedingassociated with a 2 g/dL drop in hemoglobin level or requir-ing 2 units of blood transfused, and bleeding leading to reop-eration. We separated fatal bleeding and bleeding requiringreoperation from other major bleeding events because these out-comes are the least ambiguous. We usually accepted the major


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The median rate was 1.5%, but because of the low event ratein the LMWH trials, variability in the definitions of major bleed-ing across trials makes this estimate uncertain. This is, however,consistent with a systematic review that estimated the absoluteuntreated bleeding risk to be between 1% and 2%.3

Second, we selected the major bleeding event rate for LMWHfrom a recent review that examined the reporting definitions andevent rates from the enoxaparin control arm of recent trials.40 Wechose a rate of 1.5%, which was slightly higher than the average(1.4%) and higher than 12 of 14 trials that enrolled. 16,000 patients

since 2003 that we included in the estimate of baseline VTE risk(median, 0.91%; maximum, 1.9%).4,14-26 Recognizing the some-times highly selective process of RCTs in enrolling patients withlow bleeding risk, we believe that a selected bleeding rate thatis somewhat higher than the median is therefore close to what

would be observed in clinical practice. The baseline major bleed-ing rate of 1.5% (15 of 1,000) and that expected with LMWHare shown in Table 3 and Table S1 and are very close. (Tables andfigures that contain an “S” before the number denote supplementaryinformation not contained in the body of the article and availableinstead in an online data supplement; see the “Acknowledgments”for more information.) Intuitively, a greater bleeding rate mightbe expected with the use of LMWH, but this increased risk islikely within the large CI.

1.4 VTE and Bleeding Risk Assessment

Individual risk factor assessment for VTE focuses on patient-specific characteristics, incorporating surgery-specific risk inaddition to medical factors. Alternatively, group-specific recom-mendations for thromboprophylaxis, such as major orthopedicsurgery, exist. Although individualized risk factor assessment carriesconsiderable appeal, it is limited by lack of validation in orthope-dic surgery. In addition, although we can find ORs for individualrisk factors for VTE, the interaction of these factors in a givenpatient is not well understood. Such risk factors include (multivar-iate ORs): previous VTE (OR, 3.4-26.9),41-43 cardiovascular disease(OR, 1.4-5.1),41,42 Charlson comorbidity index 3 (OR, 1.45-2.6),41,44 BMI. 25 kg/m2 (OR, 1.8),43 age (OR, 1.1 for each 5-year increment

The untreated baseline risk for the extended, out-of-hospitalperiod, defined as the time period starting at around postopera-tive day 15 and extending up to 35 days, is likely to be somewhatlower because the VTE risk is highest close to surgery and themedian time of diagnosis for thromboembolic events is 7 daysafter TKA and 17 days after THA.27 We found only one trial thatenrolled patients after 2003 that examined extended, out-of-hospital prophylaxis using a placebo group control to estimate thebaseline risk for this time period.4 Extracting events from the time-to-event graph and from the text, 11 of 1,207 (0.91%) symptomatic

VTE events were observed up to postoperative day 39, startingfrom the time enoxaparin was stopped at an average of 12 dayspostoperation. A trial that enrolled patients slightly before ourcutoff years (2001 and 2002) found a higher rate in the placeboarm (symptomatic VTE, 8/330 [2.4%]).28

In summary, we have estimated a symptomatic VTE rate that isabout one-half the rate observed in the immediate postoperativeperiod (1.5%; symptomatic DVT, 1%; PE, 0.5%). For this guide-line, we therefore estimated a combined 35-day untreated base-line risk for symptomatic VTE of 4.3%.

Although epidemiologic data from the early 1990s suggest thatthe cumulative 90-day symptomatic VTE risk for THA is higherthan that for TKA (2.8% vs 2.1%, respectively),27 randomized trialsfail to confirm this finding. Follow-up epidemiologic data from

the mid-1990s also demonstrated that cumulative 90-day symp-tomatic VTE rates after HFS did not exceed those reported forarthroplasty (HFS, 1.9%; THA, 2.4%; TKA, 1.7).29 We thereforeconcluded that a 4.3% combined symptomatic VTE untreatedbaseline risk for the first 35 days is the best approximation for allthree major orthopedic surgeries. Table 2 and Figure 1 present asummary of the estimated symptomatic VTE rates for this guideline.

Because VTE-related deaths were rarely observed in trialssince 2003, the data were insufficient to estimate current baselinerisk. In addition, competing risks, such as cardiovascular andinfectious causes of death, often outnumber the risk of deathfrom VTE, particularly in HFS. When pooling study data, totalmortality—because this outcome includes fatal bleeding—wasselected to better represent the overall balance of fatal events.The majority of mortal events were seen in HFS populations thatare elderly and experience considerable comorbidity.

1.3.2 Baseline Risk for Major Bleeding Events: The risk formajor bleeding with LMWH, and in particular without treatment,remains difficult to estimate because better operative techniquesmake deriving the untreated bleeding event rate from the placebogroup of past RCTs in major orthopedic surgery problematic. Toestimate untreated bleeding risk, we first determined the medianmajor bleeding event rate from the placebo (or graduated com-pression stockings [GCS]) arm of LMWH trials and the Pul-monary Embolism Prevention (PEP) trial (subgroup that did notreceive any heparin) because those trials were more recent.30-39

Table 2 —[Section 1.3.1] Estimated Nonfatal, SymptomaticVTE Rates After Major Orthopedic Surgery

InitialProphylaxis,

PostoperativeDays 0-14

ExtendedProphylaxis,

PostoperativeDays 15-35

Cumulative,Postoperative

Days 0-35

No prophylaxis VTE 2.80%(PE 1.00%,DVT 1.80%)

VTE 1.50%(PE 0.50%,DVT 1.00%)

VTE 4.3%(PE 1.50%,DVT 2.80%)

LMWH VTE 1.15%(PE 0.35%,DVT 0.80%)

VTE 0.65%(PE 0.20%,DVT 0.45%)

VTE 1.8%(PE 0.55%,DVT 1.25%)

See Table 1 legend for expansion of abbreviations.

Figure 1. [Section 1.3.1] Schematic of estimated incidence ratesfor LMWH and no prophylaxis for major orthopedic surgery usedfor this guideline. Additional example data are from observationalstudies (dashed line), which usually represents a cumulative inci-

dence rate resulting from high rates of prophylaxis in the first 7 to14 days and low rates or no prophylaxis during the extended pro-phylaxis period. LMWH5 low-molecular-weight heparin.



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T a b l e 3 — [ S e c t i o n 2 . 1 . 1 ] S u m m a r y o f F i n d i n g s : L M W H v s N o L M W H ( W i t h o r W i t h o u t G C S i n B o t h G r o u p s ) f o r M a j o r O r t h o p e d i c S u r g e r

y ( I n i t i a l P r o p h y l a x i s

P e

r i o d U p t o 1 4 D a y s ) 3 1 - 3 9 , 4 7 - 5 0

O u t c o m e s

N o . o f P a r t i c i p a n t s

( S t u d i e s )

Q u a l i t y o f t h e

E v i d e n c e

( G R A D

E )

R e l a t i v e E f f e c t ( 9 5 % C I )

A n t i c i p a t e d A b s o l u t e E f f e c t s

R i s k W i t h N o L M W H G

C S

R i s k D i f f e r e n c e W i t h

L M W H G

C S ( 9 5 % C I )

N o n f a t a l P E

2 , 0 2 5 ( 1 1 s t u d i e s )

H i g h

R R 0 . 5 8 ( 0 . 2 2 - 1 . 4 7 )

S t u d y p o p u l a t i o n

1 1 p e r 1 , 0 0 0

C o n t e m p o r a r y p o p u l a t i o n ( i n i t i a l p r o p h y l a x i s ) a

1 0 p e r 1 , 0 0 0

4 f e w e r p e r 1 , 0 0 0

( f r o m 8 f e w e r t o 5 m o r e )

S y m p t o m a t i c D V T ( a s i n f e r r e d f r o m

a s y m p t o m a t i c D V T )

2 , 2 5 0 ( 1 4 s t u d i e s )

M o d e r a t e b d u

e

t o i n d i r e c t n

e s s

R R 0 . 5 ( 0 . 4 3 - 0 . 5 9 )


4 6 3 p e r 1 , 0 0 0

C o n t e m p o r a r y p o p u l a t i o n ( i n i t i a l p r o p h y l a x i s ) a

1 8 p e r 1 , 0 0 0

9 f e w e r p e r 1 , 0 0 0

( f r o m 7 f e w e r t o 1 0 f e w e r )

B l e e d i n g r e q u i r i n g r e o p e r a t i o n

0 ( 0 )

M a j o r n o n f a t a l b l e e d i n g

1 , 9 7 7 ( 1 1 s t u d i e s )

M o d e r a t e c d u

e

t o i m p r e c i s

i o n

R R 0 . 8 1 ( 0 . 3 8 - 1 . 7 2 )

1 5 p e r 1 , 0 0 0

3 f e w e r p e r 1 , 0 0 0

( f r o m 9 f e w e r t o 1 1 m o r e )

T o t a l m o r t a l i t y d

9 7 1 ( 6 s t u d i e s )

M o d e r a t e c d u

e

t o i m p r e c i s

i o n

R R 0 . 9 ( 0 . 3 - 2 . 6 7 )

1 4 p e r 1 , 0 0 0

1 f e w e r p e r 1 , 0 0 0

( f r o m 1 0 f e w e r t o 2 4 m o r e )

G C S 5 g r a d u a t e d c o m p r e s s i o n s t o c k i n g s ;

G R A D E 5 G r a d e s o f R e c o m m e n d a t i o n s , A s s e s s m e n t , D e v e l o p m e n t , a n d E v a l u a t i o n ; R

R 5 r i s k r a t i o . S e e T a b l e 1 l e g e n d f o r e x p a n s i o n o f o t h e r a b b r e v i a t i o n s .

a C o n t e m p o r a r y s u r g i c a l p o p u l a t i o n f r o m

w h i c h b a s e l i n e r i s k o f p a t i e n t - i m p o r t a n t o u

t c o m e s h a s b e e n d e r i v e d ( c o n t e m p o r a r y e r a s u r g i c a l t e c h n i q u e , e a r l y m o b i l i z a t i o n , e t c [ s e e t e x t f o r d e t a i l s o n h o w

b a s e l i n e r i s k s w e r e c a l c u l a t e d ] ) .

b I n f e r r e d f r o m a s y m p t o m a t i c D V T .

c C I i n c l u d e s b e n e fi t s a s w e l l a s h a r m s .

d D e a t h s p l a c e b o G

C S : t w o f r o m V T E , n

o n e f r o m b l e e d i n g , o n e f r o m u n e x p l a i n e d c a

u s e s , a n d f o u r f r o m o t h e r c a u s e s . D e a t h s L M

W H : o n e f r o m V T E , n o n e f r o m b l e e d i n g , n o n e f r o m u n e x p l a i n e d c a u s e s ,

a n d f o u r f r o m o t h e r c a u s e s .


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Table 4 —[Sections 1.4, 2.6, 2.8] General Risk Factors for Bleeding

• Previous major bleeding (and previous bleeding risk similar tocurrent risk)

• Severe renal failure• Concomitant antiplatelet agent• Surgical factors: history of or difficult-to-control surgical bleeding

during the current operative procedure, extensive surgicaldissection, and revision surgery

plasty31-39,47,48 and HFS.49,50 Our analysis included allstudies of LMWH vs no prophylaxis whether GCS were used in both groups because this would notaffect the relative risk observed for LMWH. Thisallowed us to make more-precise estimates for riskreduction of VTE and bleeding. We decided againstpooling across other patient groups, such as nonor-thopedic surgery patients, because of differences in

risk and technique. In those trials, LMWH usually was continued for 6 to 14 days, which coincided withdischarge from the hospital at the time those trials were conducted.

For THA or TKA, LMWH consistently reduces asymp-tomatic DVT by 50% (combined risk ratio [RR],0.50; 95% CI, 0.43-0.59). Similar results were seen intwo studies in HFS involving 218 patients.49,50 Com-bining results from all relevant studies failed to dem-onstrate or to exclude a beneficial effect of LMWHon PE (RR, 0.58; 95% CI, 0.22-1.47). On the basis ofmoderate-quality evidence, the use of LMWH for the

initial prophylaxis period (10-14 days) is expected toprevent 13 VTE per 1,000 patients undergoing majororthopedic surgery, assuming a baseline risk of 1% forPE and 1.8% for symptomatic DVT.

The definition and reporting of major bleeding wasinconsistent across studies, and the results failed todemonstrate or to exclude a detrimental effect ofLMWH on the occurrence of major bleeding (RR,0.81; 95% CI, 0.38-1.72); the 95% CI was nine fewerto 11 more major bleeding events per 1,000. Few deathsoccurred, and these were mainly seen in HFS patients;two VTE-associated deaths were seen in the placebo

groups compared with one in the LMWH arm (Table 3,Figs S1-S4, Table S1).

Extended Prophylaxis With LMWH — Observationaldata suggest that the incidence of VTE after TKA andTHA returns to the presurgical risk levels at about3 months postoperation.13,27 Extending thrombopro-phylaxis beyond 10 to 14 days, which coincided withthe duration of hospital stay in older trials, is nowused often, and recent trials have included prophy-laxis for. 30 days, particularly after THA.

Three systematic reviews51-53 have examined theeffect of extended-use LMWH vs placebo from seven

trials enrolling . 2,600 patients mainly after THA54-60 ;one trial also included TKA patients.55 Most trialsrandomized patients at discharge (which occurred6-14 days postoperation) to continue with LMWH vs placebo until postoperative days 27 to 35. Becausemost studies screened patients at discharge and onlyenrolled patients without asymptomatic DVT, someauthors have argued that the absolute event ratemay be inaccurate.51 However, as discussed in theMethods section, the relative VTE risks should notbe affected. Additionally, we are providing baselinerisks based on contemporary practice.

vs age , 40 years),29 advanced age 85 years (OR, 2.1),43 vari-cose veins (OR, 3.6),42 and ambulation before day 2 after surgery(OR, 0.7).42

However, for major orthopedic surgery, the surgery-specificrisk far outweighs the contribution of the patient-specific factors.For instance, a population-based case-control study looked at635 patients with first-time VTE during a period from 1976 to1990 compared with controls.45 The factor hospitalized with recentsurgery resulted in an OR of 22 (95% CI, 9-50). In our view, indi-

vidual risk estimation is not sufficiently secure to mandate different

recommendations for different risk strata.Similarly, we did not find any bleeding risk assessments that

have been sufficiently validated in the orthopedic surgery pop-ulation. Table 4 lists general risk factors for bleeding in the settingof orthopedic surgery, but specific thresholds for using mechan-ical compression devices or no prophylaxis instead of anticoagu-lant thromboprophylaxis have not been established.

1.5 Values and Preferences

Both symptomatic VTE and bleeding are important, unwantedoutcomes from the perspective of a patient. There is little infor-mation available on the opinion of patients regarding the relativedisutility of these two outcomes. This is, however, a very impor-

tant consideration because many of the approaches to reducingpostoperative VTE use anticoagulants, and these all increase therisk of bleeding. Therefore, it is critical to judge the relative bal-ance of disutility between an episode of symptomatic VTE andof bleeding. To do this, we used available literature and the resultsof a rating exercise of physicians involved in developing theAntithrombotic Therapy and Prevention of Thrombosis, 9th ed:American College of Chest Physicians Evidence-Based ClinicalPractice Guidelines recommendations.46 On balance, it wasbelieved that the adverse consequences of a major postoperativebleeding event were approximately equal to those of symptomatic

VTE. In developing recommendations, we therefore consideredthese as equivalent in their aversiveness or disutility.

2.0 Patients Undergoing MajorOrthopedic Surgery: THA, TKA, HFS

2.1 Thromboprophylaxis ComparedWith No Prophylaxis

2.1.1 LMWH vs No Prophylaxis—Initial andExtended-Period Prophylaxis: LMWH has becomethe thromboprophylaxis agent against which newerdrugs are compared. Several studies published in themid-1980s, during the 1990s, and as recently as 2008have investigated LMWH compared with no prophy-

laxis in.

2,000 patients to test the hypothesis thatLMWH decreases the incidence of VTE after arthro-



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with a trend toward increased bleeding (RR, 1.50;95% CI, 0.92-2.43), which was described as woundhematomas, wound bleeding, wound leakage, hema-turia, and hematemesis. There was also more bloodtransfused and one intracerebral hemorrhage in the VKA group.61 Results showed a trend toward a mor-tality reduction (RR, 0.76; 95% CI, 0.54-1.07). Based onmoderate-quality evidence, VKA prophylaxis for 10 to

14 days would result in 18 fewer VTEs and seven moremajor bleeding events per 1,000 (Table 7, Table S4).

2.1.4 Aspirin vs No Prophylaxis—Initial PlusExtended Prophylaxis Period: Aspirin is inexpen-sive, orally administered, and widely available. In the1970s and 1980s, a number of studies investigatedthe use of aspirin in THA,10,62-65 TKA,66 and HFS.67-72 Those studies used high doses of aspirin of up to3.8 g daily. They suffer from serious methodologiclimitations, including the use of an unreliable methodfor DVT screening, such as fibrinogen uptake; lack

of blinding; and lack of allocation concealment. Addi-tionally, there was strong evidence of reporting andpublication bias.

Because of this low quality of evidence, a subse-quent trial, PEP, was initiated to study the effects of160 mg of aspirin given for 35 days against placebo ina routine practice setting that allowed for additionalantithrombotic intervention if deemed necessary.30 This multicenter trial enrolled 17,444 patients pre-dominantly after HFS in the mid-1990s and includedpatients after hip arthroplasty. This study has beencriticized because of perceived changes in the pri-

mary outcome and adjustments of sample size. There were additional problems with the presentation ofthe results that made evaluation of the bleeding endpoint difficult. The PEP study, however, had consid-erable strengths, including concealment of allocationthrough remote randomization; blinding of patients,caregivers, and investigators; and an independent,blinded adjudication committee that interpreted objec-tively confirmed end points, such as venographically orDUS-confirmed DVT, high probability ventilation/ perfusion scans, or pulmonary angiograms. In addi-tion, there was near-complete follow-up (99.6%).

Although the combined results (arthroplasty andHFS) failed to demonstrate or exclude a beneficialeffect of aspirin on nonfatal PE, there was a modest28% relative risk reduction in symptomatic DVT (RR,0.72; 95% CI, 0.53-0.96). The upper boundary of theCI crosses a threshold of 10% that clinicians con-sider the desirable minimum clinical effect, and theCI of the absolute effect includes as few as one lessDVT in 1,000. The results, therefore, are impre-cise, despite the large number of patients enrolled.Although there were 19 VTE-associated deaths inthe aspirin group compared with 45 in the placebo

No PE was observed in the LMWH group compared with five of 1,104 in the placebo group. Symptom-atic DVT was reduced by more than one-half (RR, 0.46;95% CI, 0.26-0.82). Results failed to demonstrateor exclude an effect of LMWH on major bleeding(RR, 0.43; 95% CI, 0.11-1.65) or on total mortality(RR, 0.39; 95% CI, 0.08-1.98), although the only twodeaths from VTE were in the placebo group. On

the basis of high-quality evidence, extending throm-boprophylaxis up to 35 days postoperation compared with 10 to 14 days will result in nine fewer symptomatic VTE per 1,000 without an appreciable increase inmajor bleeding (Table 5, Figs S5-S8, Table S2).

2.1.2 LDUH vs No Prophylaxis—Initial ProphylaxisPeriod: Numerous RCTs examined LDUH vs noprophylaxis throughout the 1970s and early 1980s.A systematic review involving close to 7,000 patientsdemonstrated a relative risk reduction of 58% (RR,0.42; 95% CI, 0.36-0.50) in the incidence of asymp-

tomatic DVT found by screening across 57 trials fromsurgical and nonsurgical populations.3 Only four of the12 studies in orthopedic surgery used venography toconfirm thrombotic events; the others used fibrinogenuptake. The relative effect estimates were similar forthe eight studies involving . 500 patients under-going elective hip replacement (RR, 0.53; 95% CI,0.32-0.89) and six trials in HFS (RR, 0.56; 95% CI,0.39-0.81) compared with the entire population.

A significant reduction in PE was observed by pool-ing all trials from surgical and nonsurgical popula-tions (RR, 0.69; 95% CI, 0.49-0.99). Unfractionated

heparin (UFH) was associated with a trend toward anincreased risk of major bleeding (RR, 1.26; 95% CI,0.99-1.6). Using our estimates of baseline risk, therelative effect translates into a reduction of 13 symp-tomatic VTEs per 1,000 with UFH, with an increasein major bleeding events of four per 1,000. Mortalevents in major orthopedic surgery were only reportedfor HFS trials (RR, 0.96; 95% CI, 0.55-1.67), and acrossall patient groups, UFH appeared to have little or noeffect on overall mortality (RR, 0.91; 95% CI, 0.8-1.04).The underlying quality of evidence was moderate(Table 6, Table S3).

2.1.3 Vitamin K Antagonist vs No Prophylaxis—Initial Prophylaxis Period: Evidence for use of vita-min K antagonists (VKAs) comes from eight RCTsinvolving 703 patients, most with hip fracture, thatdemonstrated a 55% relative risk reduction in primarilyasymptomatic DVT (RR, 0.45; 95% CI, 0.32-0.62).3 PEs were reduced by almost 80% (RR, 0.21; 95% CI,0.08-0.53), although this result is based on only32 events. Although patients and clinicians in thosetrials were not blinded, two trials blinded the throm-bosis outcome adjudicators. VKA use was associated


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T a b l e 5 — [ S e c t i o n 2 . 1 . 1 ]

S u m m a r y o f F i n d i n g s : L M W H f o r E x t e n d e d P r o p h y l a x i s v s P l a c e b o A f t e r M a j o r O r t h o p e d i c S u r g e r y ( U p t

o 3 5 D a y s ) 5 2 , 5 3

O u t c o m e s


( S t u d i e s )

Q u a l i t y o f t h e E v i d e n c e

( G R A D E )



R i s k W i t h P l a c e b o

R i s k D i f f e r e n c e W i t h L M W H f o r

E x

t e n d e d P r o p h y l a x i s ( 9 5 % C I )

N o n f a t a l P E

2 , 4 2 3 ( 6 s t u d i e s )

H i g h

R R 0 . 2 4 ( 0 . 0 4 - 1 . 4 )

S t u d y p o p

u l a t i o n

5 p e r 1 , 0 0 0

C o n t e m p o r a r y p o p u l a t i o n

( e x t e n d e d p r o p h y l a x i s ) a

5 p e r 1 , 0 0 0

4 f e w e r p e r 1 , 0 0 0


S y m p t o m a t i c D V T

2 , 6 4 7 ( 7 s t u d i e s )

H i g h

R R 0 . 4 6 ( 0 . 2 6 - 0 . 8 2 ) b

S t u d y p o p

u l a t i o n

3 3 p e r 1 , 0 0 0

C o n t e m p o r a r y p o p u l a t i o n

( e x t e n d e d p r o p h y l a x i s ) a

1 0 p e r 1 , 0 0 0

5

f e w e r p e r 1 , 0 0 0

( f r o m 2 f e w e r t o 7 f e w e r )

B l e e d i n g r e q u i r i n g r e o p e r a t i o n

0 ( 0 )

M a j o r n o n f a t a l b l e e d i n g

2 , 7 2 5 ( 7 s t u d i e s c )

H i g h d

R R 0 . 4 3 ( 0 . 1 1 - 1 . 6 5 )

5 p e r 1 , 0 0 0 e

3

f e w e r p e r 1 , 0 0 0


T o t a l m o r t a l i t y f

2 , 7 2 5 ( 7 s t u d i e s c )

H i g h d

R R 0 . 3 9 ( 0 . 0 8 - 1 . 9 8 )

2 p e r 1 , 0 0 0

1

f e w e r p e r 1 , 0 0 0


S e e T a b l e 1 a n d 3 l e g e n d s f o r e x p a n s i o n o

f a b b r e v i a t i o n s .

a C o n t e m p o r a r y s u r g i c a l p o p u l a t i o n f r o m




b N u m b e r o f e v e n t s t a k e n d i r e c t l y f r o m H u l l e t a l 5 2 b u t r e l a t i v e r i s k r e c a l c u l a t e d u s i n g

r a n d o m - e f f e c t s m o d e l .

c T h i s o u t c o m e w a s n o t p r e s e n t e d i n a f o r e

s t p l o t i n t h e o r i g i n a l m e t a - a n a l y s i s . D a t a w e r e r e e x t r a c t e d f r o m t h e o r i g i n a l p u b l i c a t i o n

f o r t h i s o u t c o m e a n d p o o l e d u s i n g a fi x e d - e

f f e c t s m o d e l ( s a m e m e t h o d a s

p r e s e n t e d i n t h e o r i g i n a l p u b l i c a t i o n ) .

d N o t d o w n g r a d e d f o r i m p r e c i s i o n b e c a u s e

C I a r o u n d a b s o l u t e e v e n t s i s n a r r o w .

e A l l e v e n t s w e r e d r o p i n h e m o g l o b i n l e v e l o f 2 g / d L .

f D e a t h s p l a c e b o : t w o f r o m V T E a n d o n e f

r o m o t h e r c a u s e s . D e a t h s L M W H : d e a t h f r o m o t h e r c a u s e s ( p n e u m o n i a ) .



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T a b l e 6 — [ S e c t i o n 2 . 1 . 2 ] S u m m

a r y o f F i n d i n g s : L D U H v s N o T h r o

m b o p r o p h y l a x i s f o r M a j o r O r t h o p e

d i c S u r g e r y ( I n i t i a l P r o p h y l a x i s P e r i o d U p t o 1 4 D a y s ) 3

O u t c o m e s

N o . o f P a r t i c i p a n t s ( S t u d i e s )

Q u a l i t y o f t h e

E

v i d e n c e ( G R A D E )



R i s k W i t h N o L D U H

R i s k D i f f e r e n c e W i t h

L D U H ( 9 5 % C I )

P E

3 , 4 2 4 ( 2 0 s t u d i e s )

M o d e r a t e a , b d u e t o i m p r e c i s i o n

R R 0 . 6 9 ( 0

. 4 9 - 0 . 9 9 )


6 0 p e r 1 , 0 0 0

C o n t e m p o r a r y p o p u l a t i o n ( i n i t i a l p r o p h y l a x i s ) c

1 0 p e r 1 , 0 0 0

3 f e w e r p e r 1 , 0 0 0

( f r o m 0 f e w e r t o 5 f e w e r )

S y m p t o m a t i c D V T ( a s i n f e r r e d f r o m

a s y m p t o m a t i c D V T )

6 , 9 8 7 ( 5 7 s t u d i e s )

M o d e r a t e d - f d u e t o i n d i r e c t n e s s

R R 0 . 4 2 ( 0

. 3 6 - 0 . 5 )


2 8 9 p e r 1 0 0 0

C o n t e m p o r a r y p o p u l a t i o n ( i n i t i a l p r o p h y l a x i s ) c

1 8 p e r 1 , 0 0 0

1 0 f e w e r p e r 1 , 0 0 0

( f r o m 9 f e w e r t o 1 2 f e w e r )

B l e e d i n g r e q u i r i n g r e - o p e r a t i o n

0 ( 0 g )

M a j o r b l e e d i n g

6 , 6 6 9 ( 4 9 s t u d i e s )

M o d e r a t e h , i d u e t o i m p r e c i s i o n

R R 1 . 2 6 ( 0

. 9 9 - 1 . 6 )


3 1 p e r 1 , 0 0 0

C o n t e m p o r a r y p o p u l a t i o n ( i n i t i a l p r o p h y l a x i s ) j

1 5 p e r 1 , 0 0 0

4 m o r e p e r 1 , 0 0 0


T o t a l m o r t a l i t y

1 2 , 6 8 2 ( 1 0 s t u d i e s )

M o d e r a t e i , k d u e t o i m p r e c i s i o n

R R 0 . 9 1 ( 0

. 8 - 1 . 0 4 )

6 6 p e r 1 , 0 0 0 l

6 f e w e r p e r 1 , 0 0 0

( f r o m 1 3 f e w e r t o 3 m o r e )

S e e T a b l e 1 a n d 3 l e g e n d s f o r e x p a n s i o n o

f a b b r e v i a t i o n s .

a O n l y o n e - t h i r d o f t h e e v e n t s f r o m s t u d i e s i n o r t h o p e d i c s u r g e r y . N o t d o w n g r a d e d f o r

i n d i r e c t n e s s b e c a u s e e f f e c t s i m i l a r t o e f f e c t o b s e r v e d .

b C I i n c l u d e s z e r o f e w e r e v e n t i n 1 , 0 0 0 .

c C o n t e m p o r a r y s u r g i c a l p o p u l a t i o n f r o m




d M a j o r i t y o f t r i a l s u s e d fi b r i n o g e n u p t a k e

t o d e t e c t D V T . N o t d o w n g r a d e d t o a v o i d d u

p l i c a t e d o w n g r a d i n g w i t h i n d i r e c t n e s s d u e t o a s y m p t o m a t i c e v e n t s b a s e d o n fi b r i n o g e n

u p t a k e .

e I 2 . 5

0 % ; h o w e v e r , t h e r e a r e c o n s i s t e n t l a r g e e f f e c t s a c r o s s m a n y c o n d i t i o n s . N o t d o w

n g r a d e d .

f M a j o r i t y o f e v e n t s w e r e a s y m p t o m a t i c ; n o t a p a t i e n t - i m p o r t a n t o u t c o m e ,

g T h i s o u t c o m e w a s n o t r e p o r t e d i n t h e s y s

t e m a t i c r e v i e w . S t u d i e s w e r e n o t r e e x t r a c t e d t o o b t a i n t h i s i n f o r m a t i o n .

h A s s e s s m e n t a n d r e p o r t i n g o f b l e e d i n g d i f f e r s s u b s t a n t i a l l y b e t w e e n s t u d i e s . N o t d o w n g r a d e d .

i C I i n c l u d e s h a r m s a n d b e n e fi t .

j A l t e r n a t e c o n t r o l g r o u p b l e e d i n g r a t e t o r

e fl e c t c o n t e m p o r a r y s u r g i c a l t e c h n i q u e .

k T h e m a j o r i t y o f e v e n t s o c c u r r e d i n m e d i c

a l p a t i e n t s . N o t d o w n g r a d e d f o r i n d i r e c t n e s s b e c a u s e e f f e c t w a s s i m i l a r .

l O n l y f r o m H F S s t u d i e s .


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r y ( I n i t i a l P r o p h y l a x i s P e r i o d U p t o

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R i s k W i t h N o V K A

R i s k D i f f e r e n c e W i t h V K A ( 9 5 % C I )

P E

6 1 0 ( 5 s t u d i e s )

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